Basic {60 -nortricyclyl-(3)-benzyl ether, and the salts thereof

ABSTRACT

The present invention is related to certain new basic Alpha nortricyclyl-(3)-benzyl ethers and salts, quaternary ammonium salts and N-oxides thereof, pharmaceutical composition comprising the same as active principle and a process for the treatment of spasm.

United States Patent I Arnold et al. [4 1 Aug. 22, 11972 [54] BASIC a-NORTRlCYCLYL-(3)-BENZYL [58] Field of Search ..260/570.6, 567.6, 501.17

ETHER, AND THE SALTS THEREOF [72] Inventors: Herbert Arnold, Bielefeld; Norbert [56] References Cited Brock, Uerentrup; Engelbert Kuhas, UNlTED STATES PATENTS Gadderbaum; Dieter Lenke, I g l f Hans pohle, Brackwede, 2,812,327 11/1957 Ohnacker et al...260/570.6X n f Germany 2,914,561 11/1959 Allen et al. ..260/570 71,001 21961 P 1' t 1 60 73 Assignee: ASTA-WERKE Aktiengesellschaft 2 9 elopo I e a 2 /567 6 X Chemische Fabrik, Brackwede OTHER PUBLICATIONS westphaha Germany Burger, Medicinal Chemistry 2nd Ed, pages 38, 22 Filed: Aug. 21, 1969 42 and s2- 83 (1960) [2]] Appl' 857272 Primary Examiner-Robert V. Hines Attorney-Oberlin, Maky, Donnely & Renner [30] Foreign Application Priority Data Sept. 6, 1968 Germany ..P 17 93 364.1 [571 ABSTRACT The present invention is related to certain new basic U-S- Cl. E, nortri y lyl (3) benzyl ethers and alts quaternary 260/326.5 C, 260/501.15, 260/501.l7, 260/567.6 M, 260/611 A, 260/618 R,

Int. Cl ...C07c 91/16 ammonium salts and N-oxides thereof, pharmaceutical composition comprising the same as active principle and a process for the treatment of spasm.

3 Claims, No Drawings BASIC a-NOR'IRlCYCLYL-(3)-BENZYL ETHER, AND THE SALTS THEREOF It has been found that compounds having the general wherein R is hydrogen, a halogen atom, a lower alkyl group having from one to four carbon atoms, the trifluoromethyl or a lower alkoxy group having from one to four carbon atoms, R is hydrogen, a straight or branched chain alkyl group having from one to four carbon atoms or the ethinyl group, alk is CH -CH CH or and A is the groupment having the formula wherein R and R represent lower alkyl groups having from one to four carbon atoms or, together with the nitrogen atom to which they are bound, represent the piperidino, morpholino or the pyrrolidino group and R is hydrogen or the methyl or ethyl group,

or A

wherein R is a lower alkyl group having from one to four carbon atoms, and the acid addition salts, quaternary ammonium salts and N-oxides thereof, have valuable properties, in particular as therapeutically active compounds.

Acid addition salts of the compounds of formula I are in particular those of pharmacologically acceptable acids.

Quaternary salts of the compounds of formula I are in particular those deriving from alkyl halides, in particular chlorides and bromides, and alkyl sulfates having one or two carbon atoms in the alkyl group.

Because of their particular good properties such compounds of formula I are preferred wherein R is hydrogen, fluorine, chlorine or bromine or the methyl,

methoxy or trifluoromethyl group, R is hydrogen, the methyl or ethinyl group, -alk is the methylene or the ethylene group, and R R and R,,, which may be identical or different from each other, represent methyl or ethyl groups.

Preferred acid addition salts are those deriving from hydrochloric, sulphuric, phosphoric, acetic, glycolic, lactic, malic, succinic, tartaric, citric, benzoic, B- hydroxy-napthoic and embonic acid. Particularly preferred are the hydrochlorides.

The compounds of the general formula I and the acid addition and quaternary salts and N-oxides thereof are effective as spasmolytics and, as long as they represent tertiary amines, antiallerg'ics, antidepressives and tremor inhibitors.

The compounds have been tested locally on the small intestine of guinea-pigs according to N. BROCK, D. LORENZ and H. BARTLING, Arch. exp. Path. Pharmakol. 215, (1952), pgs. 512 to 524. The tested compounds have been applied intravenously. The effective dose DE has been determined as that dose which reduces for 75 percent spasms caused by administration of Neostigrnine or barium chloride.

The results are as follows:

a. Tertiary amines (Table l In comparison to the known similar endocyclic product E, the compounds A and B according to the present invention are myotrop-spasmolytically three to four times more effective (BaCl spasm). The neurotrop-spasmolytical effectiveness of B corresponds to that of the known compound E while compound A is four times more effective (Neostigmine spasm). The further known comparative test compounds Avacan and Papaverine have been less effective than compounds A, B and E.

b. Quaternary ammonium salts (Table 2):

The tested quaternary ammonium compounds are characterized by a particularly high spasmolytic activity.

With respect to the neurotrop-spasmolytical effectiveness compound F according to the present invention has been more effective for 32 percent and compound G according to the present invention has been effective 93 percent more effective than the known comparative test compound ciclonium bromide.

With respect to the spasm caused by barium chloride, compound G has been twice as effective and compound F has been 25 percent more effective than ciclonium bromide. Compound G according to the present invention has been more effective than the further known comparative test compound methanteline bromide both with respect to the musculotropand the neurotrop-spasmolytic effectiveness. The neurotrop-spasmolytic effectiveness of compound F according to the present invention also has been significantly higher than that of the known compound methantelinc bromide.

TABLE 1.SPASMOLYIIC EFFECTIVENESS OF TERTIARY AMINES Spasin caused by Ncostigmin Spasm caused by BaClz Relative effectivencss calculated to the test compound Rclativc effectiveness calculated to the test compound [)E 75 1: DE 75 E=1.00

'lcst compound l\lg./kg. ,uMol/kg. i\lg./kg. pMol/kg. MgJkg. Mel/kg. MgJkg. MOI/kg.

A. 0.7-1 .2, 48 4. 73 l. 03 0. 72 2. 40 4. 86 4.17 IL 1.80 0.22 1.21 1.08 0. 00 3.17 3.54 3.15 l. 18. 0 55, 8 0.10 0. 18 20 G0 0. 13 0. 14 l) Av. an -t.l 10.4 (I. 0. U6 7. 3 18.0 0. 48 0. 54 IL 024.001 3.5 10.0 1.00 1.00 3.5 10.0 1.00 1.00

Upon injection tlyspncu, sometimes of svvcrc nature, at all doses.

Spasm caused by N eostigmin Spusm caused by BnClz Relative effective- Rclntivo effectiveness calculated to uoss calculated to the test compound the test compound DE 75 J=1 DE 75 Test compound Mg./kg. Mol/kg. Mg./kg. Moi/kg. MgJkg. lt lol/kg. Mg./kg. Mol/kg.

F 5213; 0. 13 0. 41 1. 69 1.32 v 0. 2B 0. 88 1. 57 1.25 G 5238 0.093 0. 28 2.37 1. 93 0. 18 0. 54 2. 44 2.04 H Methantclin bromide 0. 26 0. 62 0. 85 0. 87 0. 37 0. s8 1. 19 1. 25 J Ciclonium bromide (024.014) 0.22 0. 64 1.00 1.00 0. 44 1. 1 1. l. 00

The product names given in the first column of Tables l and'2 have the following significance: lIN\ Symbol Significance Compound 5212: fl-diethylamino-ethyl-[anortricyclyl-(B )-benzyl] ether hydrochloride; product according to Example 1' Compound 5237: B-diethylamino-ethyl-[amethyl-a nortricyclyl-(ii )-benzyl]-ether hydrochloride; product according to 5 Example 5 Pupuvcrin Avacan a-(fi-diethylamino-ethyl)- phenylacetic acid isoamyl ester hydrochloride; Example 1' of German Patent Nr. 842,204

Compound 024.002: B-diethylamino-ethyl- (2,5-endomethylene-A -tetrahydroarnethyl-benzhydryDether hydrochloride; lgigaz mple 7 of German Patent Nr. 1 052 Compound 5213 fl-diethylamino-ethyl [anortricyclyl-(3)-benzyl] ether bromomethylate, product according to Example 10 Compound 5238: fl-diethylamino-ethyl [d- .methyl-a-nortricyclyl-(3 )'-benzyl] ether bromomethylate, product according to Example 5 Methanteline bromide: xanthene-9- carboxylic acid-3-diethylamino-ethyl ester bromomethylate Ciclonium bromidezfl-diethylaminoethyl (2,5-endomethylene-A -tetrahydro-amethyl-benzhydryl) ether bromomethylate The compounds according to the general formula 1 and the acid addition salts and quaternary ammonium salts and'N-oxides thereof are produced by reacting a compound of the general formula 11 with a compound of the general formula III Y-alk--A in the presence of an acid binding agent at an elevated temperature, in the above general formulas II and 111 R R, and -aIk-- having the same meaning as in for mula I, X representing a halogen atom, where Y represents a hydroxy group, or X representing the hydroxy group, where Y is a halogen atom, and A, has the same meaning as A in formula I or is the groupment Cl-1 Hal, Hal being a halogen atom,

and, if A1 is the grouprnent --Cl-l l-1al, reacting the resulting compound .with a secondary amine of the general formula IV wherein R and R have the same meaning as in the general formula I, in the presence of an acid binding agent at an elevated temperature and, if desired, converting the thus ob tained compounds of formula I in an acid addition salts or an N-oxide or, by reaction with an alkyl halide or an alkyl sulfate, into a quaternary ammonium compound.

The process which gives the best results and therefore is preferred, starts with such compounds of the general formula 11, wherein X is the hydroxy group, and a compound of the general formula III, wherein Y is a halogen atom, preferably a chlorine or bromine atom.

The conversion of the compounds of formula I into the corresponding N-oxides is effected by subjecting the compounds of formula 1 to reaction with hydrogenperoxide or with a peroxy acid such as peroxy acetic or benzoic acid. I The preferred acid binding agents are metallic sodium, sodium hydride, sodium amide, sodium oxide, sodium or potassium hydroxyde or sodium or potassiurn alcoholates.

Preferably, the reaction is carried out in a suitable inert organic solvent such as benzene, toluene or xylene.

Preferably, the reactions are carried out at anor illustrate the EXAMPLE 1 B-Diethylamino ethyl [a-nortricyclyl-(B )-benzyl] ether 200 g. of a-nortricyclyl-(3)-benzyl alcohol are added with stirring to a suspension of 49 g. of sodium amide in 1,200 ml. of toluene. After standing for 10 minutes, the reaction mixture is heated to boiling and 170 g. of B- diethylaminoethyl chloride are added thereto slowly. The reaction mixture then is refluxed with stirring for 2 hours.

After cooling, the reaction mixture is washed with water, the toluene is distilled off arid the residue is subjected to fractional distillation in a vaccuum. BP-mo 119 1 C.

Yield: 248 g.= 84 percent of the theoretical.

For preparing the corresponding hydrochloride, the above obtained base is dissolved in anhydrous ether and a little less than the theoretical amount of hydrogen chloride dissolved in anhydrous ether is added thereto with stirring. The precipitated hydrochloride is filtered off with suction and recrystallized from ethyl acetate.

Fp.: 107- 110 C.

EXAMPLE 2' dimethylaminoethyl chloride as described in Example B.p. 110 115 C.

Yield: 93 g. 68.5 percent of the theoretical. Hydrochloride Fp.: 138 141 C. (recrystallized from ethyl acetate). N-Oxide hydrochloride: Fp.: 147 153 C.

EXAMPLE 3 B-Dimethylaminoethyl ether bromomethylate 31 g. of B-dimethylaminoethyl[a-nortricyclyl-(3)- benzyl] ether (prepared according to Example 2) are dissolved in 250 ml.-of acetone. 22 g. of methyl bromide are added thereto. The mixture is heated to boiling for 1 hour and, after cooling, 1,500 ml. of anhydrous ether are added thereto. The precipitated quaternary ammonium salt is dissolved another time in as little an amount of acetone as possible and again precipitated by the addition of ether Fp.: 168- 170 C. Yield: 35 g. 83 percent of the theoretical.

EXAMPLE 4 B-Dimethylaminoethyl [a-nortricyclyl-(3 )-benzyl] ether 100 g. of a-nortricyclyl-(3 )-benzyl alcohol and 67 g. of B-dimethylaminoethyl chloride are reacted in 700 ml. of toluene as described in Example 1. 11.5 g. of metallic sodium suspended therein is used as condensing agent.

B.p.., 108 112 C.

Yield: 9p g- 66.3 percent of the theoretical. Chloromethylate The product is produced analogous to Example 3. Fp.: 184 187 C. (recrystallized from a mixture of alcohol and ether). lodomethylate The product is produced analogous to Example 3. Fp.: 93 97 C. (recrystallized from a mixture of acetone and ether).

Methyl sulfate The product is produced analogous to Example 3.

[a-nortricycly1-( 3 )-benzyl] I Fp.: 172 174 C. (recrystallized from acetone).

EXAMPLE 5 a-methyl-a-nortricyclyl-( 3 then is heated to boiling for two hours and worked up as described in Example 1.

B.p. 130 136 C. Yield: 86 g. 81.1 percent of the theoretical.

5 Hydrochloride Fp.: 121 123 C. (recrystallized from ethyl acetate). Bromomethylate Fp.: 167 168 C. (recrystallized from a mixture of acetone and alcohol).

EXAMPLE 6 B-Piperidinoethyl [a-nortn'cyclyl-( 3 )-benzyl] ether 47.5 g. of a-nortricycyl-(3)-benzyl alcohol are added to a suspension of 27 g. of powderous potassium hydroxyde in 300 cc. of toluene. The resulting reaction mixture is heated toboiling. 44 g. of a-pipen'dinoethyl chloride are added thereto dropwise while boiling the reaction mixture. After termination of the addition the reaction mixture is heated to boiling for another two hours. After cooling, the reaction mixture is washed with water, worked up as previously described and finally subjected to fractional distillation Yield: 34 g. 46 percent of the theoretical. -P-om mm: C Hydrochloride I Fp.: 173 185 C. (recrystallized from ethyl acetate). Bromomethylate Fp.: 164 185 C. (recrystallized from a mixture of alcohol and ether).

Analogous to the previous Examples, the following further products according to the present invention have been prepared.

ample Chemical nomenclature Properties 7 fi-DimethylaminocthyHa- Base: B.P.o,oz 111111,: -115 0.;

ndrtrlcyclyl-(w-benzyl] gthosulfate: F.P.: 117 at 101.

'y-Dimcthylmnlnopropyl [a- Base: B.P.o.oa mm; INS- 0.; ilortrlcyclyl-(3)-benzy1] Hydrochloride: F.P.: 131* other. 133 0.;Bromomethylatc:

F.P.: 142-144 0.; 10(10- methylete: F.P.: 162165 0.

1L fl-Dlmethyluminolso ropyl Base: B.P.o.o5 mm; 11742 [a-nortricyc1y1-(3)- enzyl] Hydrochloride: F.P.: 136- cther. 144 0.; Bromomethylate:

F.P.: 201-203 C.

10 fi-Diethylaminoethyl [a- Base: B.P.o.o1 mmJ 1.19121 0.;

nortncyc1y1-(3)-benzy1] Bromomethylate: F.P.: 149- ether. 152900.; Citrate: F.P.: 90-

11. B-Diethylaminoethyl [a- Base: B.P.o.oi 1111 135 0.;

nortricyelyl-(li)-1J-methyl Hydrochloride: F.P.: 130- benzyl] ether. 132 0.; Bromomethylate:

12. B-Dimethylaminoethyl [a- Base: B.P.o.1 mm-I 134-137" 0,;

methyl-a-nortricyc1yl-(3)- Hydrochloride: F.P.: 148- p-chloro benzyl] ether. 151 0.

13 d-Diethylaminoethyl [01- Base: B.P-o.o5mm.1 136-142 0.;

nortrlc c1y1-(3)-p-methoxy- Hydrochloride: F.P.: 101- benzyll ether. 103 0.; Bromomethylate:

F.P.: 156-158 C.

14 fl-Diethylaminoethyfiw Bese:B.P.u.imm.:128132 0.;

nortric c1y1-(3)-o-eh1oro Hydrochloride: F.P.: 98- benzyl ether. 100 0.;Br0momethy1ate:

F.P. 128-142 C.

15 fi-Diethylaminoethylla- Base: B-P-0.01 mm.: 128132 0.;

nortrlc clyl-(3)-p-ch1oro- Hydrochloride: F.P.: 111- benzyl other. 115 0.; Bromomethylate:

16...... fi-DlethylemlnoethyHa- Base: B.P.o.2 mm; 114118 0.;

nortrlcycly1-(3)-m-trlfluoro- Hydrochloride: F.P.: 102- methyl benzyl] ether. 105 0.; Bromomethylate:

F .P. 160-162 C.

17 {3-Diethylaminoethy1[a- Base: B-P-D.1 mnL: 126132 0.;

methy1-a-n0rtricyc1yl-(3) Hydrochloride: F.P.: 117- p-fiuorobenzyl] ether. 119 0.; Bromomethylate:

18 fl-Diethylaminoethylla- Base: B-P-n.uu5 mu'LI ISA-137 C.

methyl-a-nortricyclyl-(ii)- Hydrochloride: F.P.: 147- p-bromobenzyl] ether. 160 0.; Brogionethylatez 1U B-DiethylamlnoethyHactllyl-a-nortricyclyl-(3)- benzyl] ctlier.

Base: B.P.o.1 mm.:130-133 C.; Hydrochloride: F.P.: 130- 132 0.; Bromomethylate: F.P.: 125129 C.

Example Chemical nomenclature Properties 20. fi-Diethylaminoethyl[a-(2- Base: B.l.o.na mm; 128135 (3.;

methyl-prypl)-a-nortricyclyl-(3)-benzyl] ether.

'y-Diethylamino ropyl[anortricyelyl-(3 -benzyl] ether.

22. fi-PyrrolidinoethyHa-nortricyolyl-(3)-benzyl] ether.

Hydrochloi'idm-FJK: 107-- 109" 0.; Bromomcthylate: F.P.: 132135 0.

Base: B.P.o. 2 mru.3 125132 0.; Bromomethylate: F.P.: 111- 117 0.

Base: B.P.o.o05 mm; Isl-159 0.; Hydrochloride: F.P.: 123126 0.; Bromomethylate: F.P.: 144-146" C.

Base: B.P.o.o1 mp1,: HIE-145 C.;

Hydrochloride: RR: 173- 175 0.; Bromornethylate: F.P.: 7273 O.

23. fi-MorpholinylethylM-nortricycly1-(3)-benzyl] ether.

24 B-l)ictliylaminoethylla-nor- Base: B.P-o.on mm.1 nil-119 0.;

tricycl l-(3)-o-methyl Hydrochloride: F.P.: 110- benzyl ether. 114 0.; Bromomethylato:

F.P.: 176l67 C. 25 B-[N-methyl-pyrrolidyl-(2)] Base: B.P.o mm; 140-145 C.

Hydrochloride: F.l.: 143- chlor-benzyl] ether. 147 0.

The above components are passed through a stainless steel sieve having a mesh width of 1 mm. and are mixed thoroughly for 30 minutes. The resulting product is pressed without previous granulation to kernels weighing 90 mg. and having diameter of 6 mm. and a radius of dishing of 5 mm.

These kernels then are coated in usual manners until a final weight of 165 mg. each.

EXAMPLE 27 Injection solution containing 10 mg. of active principle per 2 ml. of solution.

a. Compound according to Example 1 10.000 mg.

sodium dihydrogen phosphate monohydrate 6.254 mg.

disodium hydrogen phosphate dihydrate 3.8 mg.

bidistilled water, filled up to 1.00 ml.

b. Compound according to Example 5 10.0 mg. 2.00 ml.

bidistilled water, filled up to The compounds are dissolved in the bidistilled water useful for injection purpose without warming, passed through a sterile Seitz-EKS-filter under aseptic conditions and in a nitrogen atmosphere and are filled in white 1 or, respectively, 2 ml. ampoules.

EXAMPLE 28:

Suppositories:

a. Compound according to Example 1 mg. Witepsol H19 I980 mg. b. Compound according to Example 5 20 mg. Witepsol H 19 1980 mg.

The active compounds sieved to a grain-size of p. are suspended homogeneously in the molten Witepsol and are poured to suppositories weighing 2.0 g. each at a temperature not exceeding 42 C.

The compounds and preparations herein above described are particularly useful as spasmolyties and, as long as the active compounds are tertiary amines, as antiallergics, antidepressives, and tremor inhibitors. The treatment of spasm is effected by administering to persons suffering therefrom a pharmaceutical preparation of a compound of the general formula I, in particular a quaternary ammonium salt thereof and in particular orally in a dose of about 5 to about 20 mg. with persons suffering from the other symptoms (allergy, depression, tremors) the dose ranges from about 20 to about 50 mg. one to three times a day both for parenteral and oral administration, i.e., the total daily dose ranges from 20 to mg. The treatment in continued until the symptoms have disappeared.

In a test, a tablet containing 10 mg. of compound G of Table 2 has been administered orally to a person suffering from spasms of the intestines. About 20 minutes after the administration the pains caused by the spasms disappeared. The same amount of the same compound has been administered to a person suffering from a dyskinesia of the bile-duct. The pains caused by the spasms disappeared 20 minutes after the administration of the tablet. Still another patient suffering from spasms of the intestinal tract after ileo-colectomia obtained a dragee according to Example 26 b containing the compound G of Table 2; the spastic pains disappeared with 30 minutes; no undesirable side effects have been observed.

What we claim is:

1. A basic a-nortricyclyl-(3)-benzyl ether having the general formula I wherein R is a member selected from the group consisting of hydrogen, the halogen atoms, the lower alkyl groups having from one to four carbon atoms, the trifluoromethyl group and the lower alkoxy groups having from one to four carbon atoms, R is a member selected from the group consisting of the straight chain and branched chain alkyl groups having from one to four carbon atoms and the ethinyl group, alkis a member selected from the group consisting of and A is a member selected from the group consisting of the groupment wherein R and R represent members selected from the group consisting of the lower alkyl groups having from one to four carbon atoms and R is a member selected from the group consisting of hydrogen the methyl and the ethyl group and the acid addition salts thereof.

2. A compound according to claim 1 wherein R is hydrogen, R is a member selected from the group con- 

2. A compound according to claim 1 wherein R1 is hydrogen, R2 is a member selected from the group consisting of hydrogen and the methyl group, -alk- is the methylene group and A is the diethylaminomethylene group, and the acid addition salts thereof with pharmacologically acceptable acids.
 3. Beta -Diethylamino-ethyl-( Alpha -nortricyclyl-(3)-benzyl) ether hydrochloride. 